The regulation of energy balance involves complex interactions between peripheral signals and neural circuits that influence behavior and metabolism. Dysfunction of this energy balance regulatory system underlies obesity, a highly prevalent disorder that has an enormous toll in morbidity and mortality. Recent discoveries in this area, such as identification. of the fat-derived hormone involved in energy balance, ha created a great opportunity to advance understanding of energy balance and obesity but major questions remain unanswered. In particular, it has not been determined how the complex neural circuits involved in energy balance that are influenced by leptin interrelate with each other, and how key factors such as leptin affect metabolism through central and/or peripheral mechanisms. It is our intent, in this proposal, to use genetic, physiologic, neuroanatomic and biochemical techniques to better understand the peripheral and central circuits through which energy balance is regulated. Thereby, a more complete understanding of the integrated physiology of normal and abnormal weight regulation will emerge. Our proposal consists of four projects and three core units each project addressing a distinct, but interrelated aspect of the physiology of neural control of energy balance. Project #1 will use multiple techniques of functional neuroanatomy to identify chemically distinct neurons regulated by starvation and leptin in the arcuate nucleus, and will map the pathways by which they influence centers in the lateral hypothalamus as well as autonomic efferent pathways. Project #2 will use gene targeting and adeno associated (AAV) viral vector technology to identify the hypothalamic nuclei in which melanocortin 4 receptors and leptin receptors act to regulate metabolism. Project #3 will examine the role of melanin concentrating hormone and related neuropeptides to regulated food intake, thermogenesis and metabolism, employing single and combinatorial gene targeting models that will be studied in a range of physiological contexts. Project #4 will employ biochemical and genetic approaches to determine the ability of leptin to regulate metabolism through either central effector pathways or direct actions on peripheral tissues such as muscle or fat. Core A will be an administrative core that will monitor scientific progress and fiscal status and organize academic activities related to the Program project. Core B will be a Neuroanatomic Core that will use a variety of techniques in support of projects 1-4. Core C will be a Physiology and Assay Core that will support projects 1-4. Taken together, these projects will advanced our understanding of the basic mechanisms by which energy balance and metabolism are regulated through interactions between the periphery and the brain.